There is considerable interest in developing technetium (99mTc) labeled radio-pharmaceuticals targeted towards specific receptors. In these applications, generally a ligand is tethered to a receptor binding molecule and the 99mTc is bound to the ligand to form a chelate. The stability of the 99mTc chelate is important so that the radioactivity is delivered to the receptor and remains at the receptor site for the imaging session. Also, the size, shape and charge of the 99mTc chelate can have a dramatic effect on the interaction of the receptor binding portion of the molecule to its receptor. In addition, chelates should be designed to promote good clearance from the body and low uptake in non target organs. This is particularly critical in the development of radiotherapeutic agents, based on 188Re. Our goal is to design Tc chelates with high stability and with a variety of novel structures. We will also evaluate biodistribution in collaboration with Cornell University Medical Center. We plan to investigate the fundamental chemistry of technetium bound to peptides containing natural amino acids and non-natural amino acids in order to design a suitable chelating system for Tc. We will use three "Tc cores", all available on the tracer, 99mTc, and macroscopic, 99Tc, scales. There are [TcO]3+. [TcN]2+ and Tc(CO)/3+. We will compare Tc and rhenium chemistry of analogous systems, since Re is often used as a "surrogate" for Tc and the correspondence of the chemistry in new ligands must be established. Also 188Re has potential for radio-therapeutic applications. Our strategy consists of the following specific aims. A. We plan a systematic examination of the binding of Tc to amino acids and dipeptides to compare stabilities and structures. B. Examination of the binding of Tc to tri- and tetra-peptides will be performed. We will use traditional and non-traditional amino acids in our peptide ligands. We plan to examine the interconversions of isomers in a selected tripeptide series. C. Using information derived from A and B, we will examine the effect of positioning residues at the ends of a peptide; so that the binding to the metal ion will form a cyclic peptide. In this design, the Tc will be an "integral" portion of the molecule. To accomplish the above, we will prepare complexes, both on the tracer scale, using 99mTc, and on the macroscopic scale, using 99Tc, a weak beta-emitter and Re. We will examine stability by the use of cysteine (and other ligand) challenges to obtain a comparative scale of stabilities. The structure and solution chemistry will be examined using the macroscopic 99Tc species. Biodistribution will be performed on selected 99mTc samples and 188Re will also be incorporated into selected peptides.